This invention relates to the therapy of irritable bowel syndrome (IBS), in particular, upper irritable bowel syndrome (non-ulcerative dyspepsia), and related conditions as hereinafter described.
Irritable bowel syndrome is the most common reason for referral to gastroenterology clinics and affects 10-12% of the whole population. To date, systematic efforts to determine its aetiology have proved fruitless. No consistent biochemical or physiological abnormalities have been demonstrated and many gastroenterologists describe it as a functional disorder, without an organic basis. IBS can be described as a condition of the gastrointestinal tract characterised by a disorder of the gut motility or rate of movement along the gastrointestinal tract which may be either delayed or increased. Accordingly, IBS is not characterised by any consistent abnormality in the gut.
The degree of psychological abnormality attributed to patients with IBS varies from study to study. At the inventors' clinic, using standardised diagnostic criteria (DSM-III) (American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders) (3rd Ed. Washington D.C.: APA), approximately 30% of IBS patients have been found to have psychiatric illness, whilst others using less rigorous diagnostic criteria suggest abnormality in over 80% of such patients (Chaudhury, N.A., and Truelove, S. C., Q. J. Med. 1962; 31:307-322). A more recent study by Gomez, J. and Dally, P. (B. M. J., 1977: 1; 1451-1453) again found that almost all patients have evidence of psychiatric illness, the most common diagnosis was depression, followed by anxiety states and hysterical conversion. The high level of obsessional traits in such patients has also been stressed.
A gastrointestinal syndrome consisting of early satiety, post-prandial fullness/bloating, belching, nausea and epigastric pain in the absence of significant organic pathology is well recognised and usually described as non-ulcerative dyspepsia (NUD) (see for example, Nyren, D. et al., 1987, J. Clin. Gastroenterol. 20, 896-900). Attempts to elucidate its aetiology have failed to produce consistent pathophysiological correlates and numerous psychological theories have been postulated to explain the symptoms. The terms pseudoulcer syndrome, pyloroduodenal irritability, functional dyspepsia, nervous dyspepsia and more recently upper irritable bowel syndrome have all been used. It has a prevalence of around 20% and an annual incidence of over 1%. It is a costly condition resulting in expensive investigations and the use of empiric treatments of healing peptic ulcers.
The sympathetic division of the autonomic nervous system has long been recognised as important in the control of gastrointestinal function. Noradrenergic (NA) .alpha.-2 receptors in the hypothalamus form an important part of this network and recent research has demonstrated that these receptors have a significant influence on intestinal motility and transit time (Jiang, Q.I. et al. Gastroenterology 1988; 95: 1265-1271). The .alpha.-2 agonist clonidine acting centrally produces a dose-dependent decrease in intestinal motility (Jiang, Q,I, et al. supra).
Serotonin is a monoamine which acts both as a transmitter in the gut and centrally in the brain. It plays an important role in regulating peristalsis and intestinal tone. Some cases of functional abdominal pain have been attributed to hyperserotoninaemia (Warner, R.P., Ann. Intern. Med. 1963;59: 464-76).
Research to date indicates that there are at least three types of 5-HT receptors, 5-HT 1, 5-HT 2 and 5-HT 3. The 5-HT 1 receptor is further subdivided into 5-HT 1A, 1B and 1C. These 5-HT 1 receptors are labelled using 8-OH-DPAT.
The majority of patients with non-ulcerative dyspepsia are, however, not hyperserotoninaemic. Nonetheless, the inventors postulated that altered sensitivity of 5-HT receptors might have similar consequences to high levels of serotonin. It was thus hypothesized that serotonin or serotonergic receptors are supersensitive in non-ulcerative dyspepsia. When an experiment was carried out as hereinafter described to test this hypothesis it was found to be correct in that 70-80% of persons with non-ulcerative dyspepsia were found to have supersensitive serotonin receptors or significant down regulation of .alpha.-2 noradrenergic receptors in their brains.
Accordingly, it was postulated that the blocking of the serotonin receptors in individuals with non-ulcerative dyspepsia and related conditions would lead to alleviation or reversal of symptoms.
It is an object of the present invention to provide for effective therapy of non-ulcerative dyspepsia and related conditions.
By "related condition" herein is meant inter alia non-ulcerative dyspepsia of the dismotility type, pelvic floor syndrome and oesophageal dyspepsia which have similar symptoms to non-ulcerative dyspepsia. Hereinafter non-ulcerative dyspepsia and said related conditions will be referred to collectively as non-ulcerative dyspepsia.
It is a further object of the present invention to provide a method of diagnosing non-ulcerative dyspepsia which can be carried out without surgical intervention or other invasive method.